A Concise and Cascade Synthesis
of Batracylin and Substituted Isoindolo-[1,2-b]quinazolin-12(10H)-ones

R. Shankar; Manoj Balu Wagh; M. V. Madhubabu; N. Vembu; U. K. Syam Kumar

doi:10.1055/s-0030-1259921

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Synlett 2011(6): 844-848
DOI: 10.1055/s-0030-1259921

LETTER

A Concise and Cascade Synthesis of Batracylin and Substituted Isoindolo-[1,2-b]quinazolin-12(10H)-ones

R. Shankar^a, Manoj Balu Wagh^a, M. V. Madhubabu^a, N. Vembu^b, U. K. Syam Kumar*^a
^a Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Miyapur, Hyderabad, 500049, India
Fax: +91(40)23045439; Fax: +91(40)23045438; e-Mail: syam_kmr@yahoo.com;
^b Urumu Dhanalakshmi College, Tiruchirappalli 620019, India

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Publication History

Received 28 October 2010
Publication Date:
16 March 2011 (online)

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Abstract

A concise, highly convergent, and practical synthesis of the clinical-phase anticancer agent batracylin in a two-stage process in excellent yield is described. The B and C rings of this tetracyclic heterocycle are constructed by cascade cyclization of 5-nitro-2-aminobenzyl alcohol with 2-cyanomethyl benzoate in trifluoroacetic acid in good yield in a single-pot reaction. A plausible mechanism for the cascade reaction is also proposed. As part of these studies, a range of batracylin derivatives with different substituents on the C and D rings are synthesized.

Key words

batracylin - antineoplastic agents - cascade cyclization - 5-nitro-2-aminobenzyl alcohol

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References and Notes

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12

A solution of methyl 2-cyanobenzoate (0.5 g, 0.003 mol), 2-aminophenylmethanol (0.57 g, 0.0047 mol) in TFA (10 mL) was refluxed for 10-12 h, and the progress of the reaction was monitored by TLC. After complete disappearance of the starting material, the reaction was quenched with ice water and the aqueous layer extracted with CH₂Cl₂ (2 × 10 mL). The combined extracts washed with aq NaHCO₃ (10%, 25 mL) dried over anhyd Na₂SO₄, filtered, and concentrated under vacuum. The crude product was then purified by column chromatography using CH₂Cl₂ as an eluent; yield 0.43 g (62%).

13

Isoindolo [1,2- b ]Quinazolin-12(10 H )-one (12)
Yield 62%; mp 186 ˚C (lit. 175-177 ˚C);⁸ IR (KBr): 1724, 1650 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 7.6 Hz, 1 H, ArH), 7.90 (d, J = 6.7 Hz, 1 H, ArH), 7.74-7.63 (m, 2 H, ArH), 7.51 (d, J = 8.0 Hz, 1 H, ArH), 7.34-7.18 (m, 3 H, ArH), 5.00 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.2, 148.7, 140.0, 134.0, 133.2, 132.4, 130.1, 128.4, 127.4, 127.3, 127.2, 122.8, 121.9, 121.2, 40.2 ppm. MS: m/z (%) = 235.2 [M + H]⁺. Anal. Calcd for C₁₅H₁₀N₂O (234.2): C, 76.91; H, 4.30; N, 11.96; O, 6.83. Found: C, 76.83; H, 4.25, N, 4.26, O, 6.70.

14

8-Bromoisoindolo[1,2- b ]quinazolin-12(10 H )-one (24)
Yield 63%; mp 214 ˚C. IR (KBr): 1731, 1645 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.02 (d, J = 7 Hz, 1 H, ArH), 7.90 (d, J = 7 Hz, 1 H, ArH), 7.84-7.77 (m, 2 H, ArH), 7.57 (s, 1 H, ArH), 7.51 (dd, J = 8.2, 1.5 Hz, 1 H, ArH), 7.34 (d, J = 8.5 Hz, 1 H, ArH), 4.93 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 165.9, 149.2, 139.3, 133.7, 133.1, 132.4, 131.1, 129.8, 128.8, 124.4, 122.7, 121.9, 119.5, 40.7 ppm. MS: m/z (%) = 313.1 [M + H]⁺. Anal. Calcd for C₁₅H₉BrN₂O (311.99): C, 57.53; H, 2.90; N, 8.95; O, 5.11. Found: C, 57.48; H, 2.85; N, 8.85; O, 5.1. 7-Fluoroisoindolo[1,2- b ]quinazolin-12(10 H )-one (25) Yield 57%; mp 213 ˚C. IR (KBr): 1729, 1646 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.06 (d, J = 7.2 Hz, 1 H, ArH), 7.92 (d, J = 6.8 Hz, 1 H, ArH), 7.75-7.69 (m, 2 H, ArH), 7.22 (dd, J = 2.4, 9.6 Hz, 1 H, ArH), 7.19-7.12 (m, 1 H, ArH), 6.98-6.93 (m, 1 H, ArH), 4.95 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 166.8, 149.9, 142.1, 133.0, 132.6, 132.3, 131.6, 131.1, 130.4, 127.8, 127.7, 123.5, 123.2, 122.3, 40.3 ppm. MS: m/z (%) = 253.2 [M + H]⁺. Anal. Calcd for C₁₅H₉FN₂O (252.07): C, 71.42; H, 3.60; N, 11.11; O, 6.34. Found: C, 71.34; H, 3.50; N, 11.01; O, 6.29. 9-Methylisoindolo[1,2- b ]quinazolin-12(10 H )-one (26) Yield 54% mp 243 ˚C. IR (KBr): 1721, 1650 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.04 (d, J = 6.8 Hz, 1 H, ArH), 7.92-7.78 (m, 3 H, ArH), 7.26-7.24 (m, 2 H, ArH), 7.14-7.10 (m, 1 H, ArH), 4.85 (s, 2 H, CH₂), 2.49 (s, 3 H, CH₃) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 166.8, 148.4, 139.8, 135.4, 134.1, 132.8, 132.0, 130.4, 129.3, 128.3, 125.7, 123.1, 122.3, 119.8, 39.4, 18.1 ppm. MS: m/z (%) = 249.2 [M + H]⁺. Anal. Calcd for C₁₆H₁₂N₂O (248.09): C, 77.40; H, 4.87; N, 11.28; O, 6.44. Found: C, 77.32; H, 4.78; N, 11.19; O, 6.35.
7,8-Difluoroisoindolo[1,2- b ]quinazolin-12(10 H )-one (27) Yield 53%; mp 278 ˚C. IR (KBr): 1729, 1647 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.04 (d, J = 7.6 Hz, 1 H, ArH), 7.9 (d, J = 6.8 Hz, 1 H, ArH), 7.75-7.68 (m, 2 H, ArH), 7.34 (m, 1 H, ArH), 7.00 (t, 8.8 Hz, 1 H, ArH), 4.90 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 180.0, 158.5, 141.2, 133.2, 132.5, 130.3, 123.4, 122.4, 116.9, 115.4, 110.0, 40.3 ppm. MS: m/z (%) = 271.2 [M + H]⁺. Anal. Calcd for C₁₅H₈F₂N₂O (270.06): C, 66.67; H, 2.98; N, 10.37; O, 5.92. Found: C, 66.58; H, 2.87; N, 10.29; O, 5.83.
10-Phenylisoindolo[1,2- b ]quinazolin-12(10 H )-one (28) Yield 72%; mp 210 ˚C. IR (KBr): 1732, 1646 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.10 (d, J = 7.5 Hz, 1 H, ArH), 7.88-7.78 (m, 3 H, ArH), 7.49 (d, J = 7.0 Hz, 1 H, ArH), 7.35-7.21 (m, 8 H, ArH), 6.47 (s, 1 H, CH) ppm. ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 174.8, 165.9, 153.2, 143.1, 138.9, 133.9, 133.8, 132.8, 129.7, 128.8, 128.7, 128.1, 127.8, 127.8, 127.3, 126.4, 126.2, 123.2, 122.3, 54.5 ppm. MS: m/z (%) = 311.2 [M + H]⁺. Anal. Calcd for C₂₁H₁₄N₂O (310.11): C, 81.27; H, 4.55; N, 9.03; O, 5.16. Found: C, 81.20; H, 4.50; N, 8.92; O, 5.10.
10-Methylisoindolo[1,2- b ]quinazolin-12(10 H )-one (29) Yield 70%; mp 123 ˚C. IR (KBr): 2925, 1728, 1648 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, J = 7.6 Hz, 1 H, ArH), 7.81 (d, J = 7.2 Hz, 1 H, ArH), 7.64-7.57 (m, 2 H, ArH), 7.40 (d, J = 8.0 Hz, 1 H, ArH), 7.26-7.21 (m, 1 H, ArH), 7.18-7.15 (m, 1 H, ArH), 7.12 (d, J = 6.8 Hz, 1 H, ArH), 5.41 (q, J = 6.4 Hz, 1 H, CH), 1.51 (d, J = 6.4 Hz, 3 H, CH₃) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 167.0, 149.9, 139.8, 134.5, 132.9, 132.0, 130.6, 128.6, 127.8, 127.7, 127.7, 127.5, 123.2, 122.1, 47.9, 23.6 ppm. MS: m/z (%) = 249.2 [M + H]⁺. Anal. Calcd for C₁₆H₁₂N₂O (248.09): C, 77.40; H, 4.87; N, 11.28; O, 6.44. Found: C, 77.32; H, 4.81; N, 11.20; O, 6.36.

17

8-Aminoisoindolo[1,2- b ]quinazolin-12(10 H )-one (1) Mp 280-282 ˚C (recrystallized from CH₂Cl₂). IR (KBr): 3474, 1688, 1645 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.95 (d, J = 8.0 Hz, 1 H, ArH), 7.86 (d, J = 6.8 Hz, 1 H, ArH), 7.78-7.68 (m, 2 H, ArH), 7.13 (d, J = 8.4 Hz, 1 H, ArH), 6.52 (dd, J = 2.4, 8.2 Hz, 1 H, ArH), 6.46 (s, 1 H, ArH), 5.54 (s, 2 H, NH₂), 4.80 (s, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.9, 148.8, 143.8, 134.2, 132.8, 131.3, 129.7, 129.4, 128.8, 122.8, 122.6, 121.2, 113.2, 111.7, 40.3 ppm. MS: m/z (%) = 250.2 [M + H]⁺. Anal. Calcd for C₁₅H₁₁N₃O (249.09): C, 72.28; H, 4.45; N, 16.86; O, 6.42. Found: C, 72.19; H, 4.38; N, 16.80; O, 6.35.

Supplementary Material

Supporting Information